This invention is directed to kinases inhibitors, and more particularly to 1,5-diaryl substituted pyrazole compounds that, inter alia, inhibit the activity of mitogen-activated protein kinases, compositions of those inhibitors, intermediates for the syntheses of those compounds, and processes for treating pathological mitogen-activated protein kinase activity.
Mitogen-activated protein (MAP) kinases are a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines.
The p38 MAP kinase group is a MAP family of various isoforms, including p38, p38 and p38, and is responsible for phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-) and interleukin-1 (IL-1). The products of the p38 phosphorylation mediatethe production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.
TNF-a is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated TNF production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid arthritis. Additional studies demonstrate that inhibition of TNF has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.
IL-1 is produced by activated monocytes and macrophages and is also involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
Various pyrazoles have previously been described. For example, WO 95/33727, published Dec. 14, 1995, describes substituted pyrazoles as corticotropin-releasing factor (CFR) antagonists used in the treatment of illnesses such as stress and anxiety related disorders. WO 96/21660, published Jul. 18, 1996, describes substituted pyrazoles and their use as ligands for dopamine receptors within the body. EP 0 699 438 A2, published Mar. 6, 1996, describes pyrazoles and their use as neurotensin antagonists. U.S. Pat. No. 2,833,779, to Fields et al., describes the preparation of 1,3,5-tri-substituted pyrazoles. U.S. Pat. No. 4,957,971, to Picard et al., describes trans-6-[2-(N-heteroaryl-3,5-disubstituted)pyrazol-4-yl)ethyl- or ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones as potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, used for inhibiting cholesterol biosynthesis. U.S. Pat. No. 5,441,975, to Lee et al., describes pyrazoles that are useful for the treatment of hypercholesterolemia or atherosclerosis in mammals. WO 93/04052, published Mar. 4, 1993, describes pyrazole having ACAT inhibitory activity. U.S. Pat. No. 5,102,893, to Picard et al., describes trans-6-[2-(N-heteroaryl-3,5-disubstituted)pyrazol-4-yl)ethyl- or ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase and useful as hydrolipidemic and hypocholesterolemic agents. WO 94/22838, published Oct. 13, 1994, describes pyrazole compounds having angiotensin II antagonism which are useful in preventing or treating hypertension, congestive heart failure, chronic renal failure, aldosteronism, and increased intralocular pressure.
WO 92/19615, published Nov. 12, 1992, describes pyrazoles, pyrazolines and tetrahydropyridazine having fungicidal activity. U.S. Pat. No. 5,232,940, to Hatton et al., describes a N-Phenylpyrazole and their use against arthropod, plant nematode, helminth and protozoan pests. WO 95/01340, published Jan. 12, 1995, describes novel pyrazole compounds having agrohorticultural bactericidal effect. U.S. Pat. No. 5,201,938, to Costales, describes novel substituted N-pyrazolyl-1,2,4-triazolo[1,5-c]-pyrimidine-2-sulfonamide compounds and their use as herbicides. WO 93/09100, published May 13, 1993, describes trizolocarboxamides with herbicidal activity used to control blackgrass, wild oats, crabgrass, giant foxtail, and barnyardgrass. WO 94/29300, published Dec. 22, 1994, describes pyrazoles 3-substituted by a heterocyclic ring and their use as agricultural fungicides. WO 96/37477, published Nov. 28, 1996, describes substituted pyrazoles and their use against animal parasites and pests and as insecticides, and fungicides.
Pyrazoles have also been described for use in the treatment of inflammation. U.S. Pat. No. 5,242,940, to Wachter and Murray, describes 1,5 heterocyclic pyrazoles and their use in alleviating inflammatory and cardiovascular disorders in mammals. U.S. Pat. No. 5,134,142, to Matsuo, et al., describes 1,5 diaryl substituted pyrazoles and 1,3 diaryl substituted pyrazoles useful in the treatment of inflammation, pain, thrombosis and rheumatism. U.S. Pat. No. 5,466,823, to Talley et al., describes a class of pyrazole benzenesulfonamide compounds and their use in treating inflammation and inflammation-related disorders.
The invention""s pyrazolyl compounds are found to show usefulness, inter alia, as p38 kinase inhibitors.
In accordance with the present invention, it has been found that certain 1,5-diaryl pyrazoles are effective for inhibition of mitogen-activated protein (MAP) kinases. Mitogen-activated protein kinases are believed to be associated with, inter alia, the mediation of a number of inflammatory diseases. In particular, it has been found that these certain 1,5-diaryl pyrazoles are effective for the inhibition of the p38 MAP kinase group, a sub-family of MAP kinases. The compounds of interest here have structures that correspond to Formula I, below, whose substituent groups are defined hereinafter, or a pharmaceutically acceptable salt thereof. 
A process for treating a host mammal having a condition associated with pathological p38 MAP kinase activity is also contemplated. That process comprises administering a compound described herein in a p38 MAP kinase enzyme-inhibiting effective amount to a mammalian host having such a condition. The use of administration repeated a plurality of times is particularly contemplated.
The p38 MAP kinase sub-family have various isoforms, including p38, p38 and p38 and is responsible for phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor (TNF-) and interleukin-1 (IL-1). The products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF- and IL-1, and cyclooxygenase-2.
Excessive or unregulated TNF production has been implicated in mediating a number of diseases, including rheumatoid arthritis, inflammation, inflammatory bowel disease, multiple sclerosis, asthma, and viral infections. IL-8 is another pro-inflammatory cytokine, and is associated with conditions including inflammation. Additionally, IL-1 is involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption. TNF-, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of the production of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
As already noted, the present invention is directed to compounds that inhibit the activity of p38 MAP kinase, among other activities, as well as to processes for using such a compound in treating a condition mediated by that enzyme or TNF. One embodiment of the present invention is directed to a 1,5-diaryl pyrazole compound that, inter alia, inhibits the activity of the p38 mitogen-activated protein kinase enzyme. That compound corresponds in structure to Formula I below, or a pharmaceutically-acceptable salt thereof: 
wherein A is xe2x95x90Nxe2x80x94 or xe2x95x90CHxe2x80x94;
Ar1 is an aryl group that is optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxido, wherein the subsituent on the sulfur atom is hydrocarbyl, sulfonylamide,
wherein the substituents on the sulfonamido nitrogen atom are hydrido or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, N-monosubstituted or N,N-disubstituted aminohydrocarbyl group,
wherein the substituent(s) on the aminohydrocarbyl nitrogen atom are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group, amino, and a N-monosubstituted or N,N-disubstituted amino group,
wherein the substituent(s) on the amino nitrogen are selected from the group consisting of hydrido, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarboyl, arylsulfonyl, and hydrocarbylsulfonyl or wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group;
Z is selected from the group consisting of hydrido, hydrocarbyl, halogen, carboxy, cyano, azido, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamido, and xe2x80x94Xxe2x80x94Y wherein
xe2x80x94X is xe2x80x94O, xe2x80x94S or xe2x80x94NQ,
xe2x80x94Y is hydrido, hydrocarbyl or hydrocarbylaryl,
Q is hydrido, hydrocarbyl, hydroxylhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl;
R1 is selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and an aryl substituent that is optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbylhydroxycarbonyl-hydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N,N-disubstituted aminohydrocarbyl group,
wherein the substituent(s) on the amino-hydrocarbyl nitrogen atom are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group; and
R2 is selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and an aryl group that is substituted by one or more substituents, said one or more substituents being selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbyamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonyl-hydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N,N-disubstituted aminohydrocarbyl group,
wherein the substituent(s) on the aminohydrocarbyl nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group; and
provided that when A is xe2x95x90CHxe2x80x94 and Z is hydrido, hydrocarbyl, halogen, or hydrocarboyl:
1) Ar1 is other than an aryl group that is substituted by one or more substituents selected from the group consisting of a hydrido, halogen, hydrocarbyl, perfluorohydrocarbyloxy, nitro, perfluorohydrocarbyl, amino, aminosulfonyl, halohydrocarbyloxyhydrocarbyl, hydroxy, hydrocarbylsulfonylamino, hydrocarbylsulfonly, acetylamino, carbonylhydrocarbylamino, perfluorohydrocarbylsulfonyl, hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, hydrocarbylthio, hydroxyhydrocarbyl, arylhydrocarbyl, hydrocarbyloxyhydrocarbyl, hydrocarbyloxycarbonyl, hydrocarbyloxyarylhydrocarbyl, halohydrocarbyloxy, hydrocarbyloxyhydrocarbyl; or
2) R1 is other than hydrido, hydrocarbyl, aryl, haloaryl, cyanoaryl, hydroxyaryl, hydrocarbylaryl, cyano, perfluorohydrocarbyl, hydroxyhydrocarbyl, arylhydrocarbyl, carboxy, hydrocarbyloxycarbonyl, hydrocarboylhydrocarbyl, aminocarbonyl, arylhydrocarbyl-hydrocarboyl-hydrocarbyl monosubstituted amino carbonyl, hydrocarbyl-hydrocarboyl-hydrocarbyl monosubstituted amino carbonyl, hydrocarbyl-hydrocarbylhydrocarboyl-hydrocarbyl monosubstituted amino carbonyl, hydrocarbyl-hydroxy-disubstituted amino carbonylhydrocarbyl, or a six membered heteroaryl group substituted by a nitrogen atom; or
3) R2 is other than hydrido, carboxy, hydrocarbyloxycarbonyl, halogen, or aryl.
In particularly preferred practice, A is xe2x95x90CHxe2x80x94 so that a contemplated 5-substituent is a 4-pyridyl residue, as compared to being a 4-pyrimidyl residue.
When examined primarily on the basis of activity, Formula I includes three particularly preferred subclasses of compounds of high interest. One subclass of particular interest is a preferred class of compounds exhibit IC50 in vitro activities in the assay discussed hereinafter and shown in Table I of about 1.5 to less than ( less than ) 10 xcexcM. This embodiment comprises compounds of Formula I or a pharmaceutically acceptable salt thereof wherein:
Ar1 is an aryl group that is substituted by a group selected from fluorine, or lower hydrocarbyl;
R1 is hydrido, or lower hydrocarbyl;
R2 is selected from the group consisting of hydrido, lowerhydrocarbyl and aminocarbonyl;
Z is hydrido, or xe2x80x94Xxe2x80x94Y;
xe2x80x94X is xe2x80x94O or xe2x80x94NQ;
Q is aryl lower hydrocarbyl; and
xe2x80x94Y is hydrido or lower hydrocarbyl.
A more preferred subclass of compounds exhibit IC50 in vitro activities in the assay discussed hereinafter of about 1.0 to less than ( less than ) 1.5 xcexcM. This more preferred embodiment comprises those compounds of Formula I or a pharmaceutically acceptable salt thereof wherein:
Ar1 is an aryl group that is substituted by one or more substituents that are lower hydrocarbyl, or halo such as flourine;
R1 is hydrido, or lower hydrocarbyl;
R2 is hydrido or lower hydrocarbyl;
Z is hydrido or xe2x80x94Xxe2x80x94Y;
xe2x80x94X is xe2x80x94NQ;
Q is lower hydrocarbyl or hydroxyl lower hydrocarbyl; and
xe2x80x94Y is hydrido or lower hydrocarbyl.
The most preferred subclass of compounds of Formula I exhibit IC50 in vitro activities in the assay discussed hereinafter and shown in Table I of less than ( less than ) 1.0 xcexcM. This subclass of compounds comprise those compounds of Formula I or a pharmaceutically acceptable salt thereof wherein:
Ar1 is an aryl group that is substituted by one or more substituents that are lower hydrocarbyl or halo such as flourine or chlorine;
R1 is hydrido, or lower hydrocarbyl;
R2 is hydrido;
Z is selected cyano or xe2x80x94Xxe2x80x94Y;
wherein xe2x80x94X is xe2x80x94O, or xe2x80x94NQ;
Q is selected from a group consisting of hydrido, lowerhydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 3-pyridyl lower hydrocarbyl; and
xe2x80x94Y is hydrido, lower hydrocarbyl, or aryl lower hydrocarbyl.
It has been found that certain 1,5-diaryl pyrazoles are effective for inhibition of mitogen-activated protein (MAP) kinases. Mitogen-activated protein kinases are believed to be associated with, inter alia, the mediation of a number of inflammatory diseases. In particular, it has been found that these certain 1,5-diaryl pyrazoles are effective for the inhibition of the p38 MAP kinase group of enzymes, a sub-family of MAP.
Because of the interrelation between p38 kinase and TNF, compounds of Formula I are useful for, but not limited to, the treatment of a disorder or disease state in a human, or other mammal, that is exacerbated or caused by excessive or unregulated TNF or p38 kinase production; i.e., pathological p38 MAP kinase activity, by such mammal. Accordingly, the present invention provides not only compounds but also a method of treating a TNF-mediated disease that comprises administering an effective TNF-inhibiting amount of a compound of Formula I, or a pharmaceutically acceptable salt or tautomer thereof.
Compounds of Formula I are also useful for, but not limited to, the treatment of inflammation in a subject, and for use as an antipyretic for the treatment of fever. Compounds of the invention is useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. Such compounds are further useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpesvirus.
The compounds disclosed herein are also useful for the treatment of bone resorption diseases, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft vs. host reaction and allograft rejections, cardiovascular diseases including atherosclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection. The compounds are also useful for the treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erthrematosis (SLE), skin-related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, and scar tissue formation. Compounds of the invention are also useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. The compounds of the invention can also be useful for preventing the production of cyclooxygenase-2.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
The present compounds can also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatory agents, such as together with steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS, immunosuppressive agents, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors.
As used herein, the term xe2x80x9cTNF-mediated disorderxe2x80x9d refers to any and all disorders and disease states in which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, is therefore considered a disorder mediated by TNF.
As used herein, the term xe2x80x9cp38-mediated disorderxe2x80x9d refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to p38, is therefore considered a disorder mediated by p38.
As TNF- has close structural homology with TNF (also known as cachectin), and because each induces similar biologic responses and binds to the same cellular receptor, both TNF- and TNF- are inhibited by the compounds of the present invention and thus are herein referred to collectively as xe2x80x9cTNFxe2x80x9d unless specifically delineated otherwise.
When examined first on the basis of structure and then functional activity among the 5-(4-pyridyl) pyrazole substituents, one observes three further subclasses of particularly preferred compounds within the compounds of Formula I. One subclass of particularly preferred compounds has structures that are represented by Formula II, below, or a pharmaceutically acceptable salt thereof: 
wherein R3 is hydrido, or C1-C6 (lower) hydrocarbyl;
R4 is selected from a group consisting of hydrido, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2-pyridyl lower hydrocarbyl, 3-pyridyl lower hydrocarbyl or 4-pyridyl lower hydrocarbyl;
Ar1 is an aryl group that is substituted by a halogen or halo group (e.g., chlorine, fluorine and bromine), lower hydrocarbyl, or hydrocarbyloxy group;
R1 hydrido, or C1-C6 hydrocarbyl; and
R2 is hydrido, or lower hydrocarbyl.
One preferred group of compounds of Formula II noted in Table I exhibit IC50 in vitro activities in the assay discussed hereinafter of less than ( less than ) 10 and greater than ( greater than ) 1.5 xcexcM. This group of compounds comprises those compounds of Formula II or a pharmaceutically acceptable salt thereof wherein:
Ar1 is an aryl group that is substituted by lower hydrocarbyl;
R1 is lower hydrocarbyl;
R2 is hydrido;
R3 is hydrido or C1-C6, hydrocarbyl; and
R4 is C1-C6 hydrocarbyl or aryl lower hydrocarbyl.
A more preferred class of compounds of Formula II noted in Table I exhibits IC50 in vitro activities in the assay discussed hereinafter of about 1.0 to less than ( less than ) 1.5 xcexcM. This group of compounds is comprised of those compounds of Formula II or a pharmaceutically acceptable salt thereof wherein:
Ar1 is an aryl group that is substituted by lower hydrocarbyl;
R1 is lower hydrocarbyl;
R2 is hydrido;
R3 is hydrido or lower hydrocarbyl; and
R4 is lower hydrocarbyl, or hydroxyl lower hydrocarbyl.
The most preferred class of compounds of Formula II noted in Table I exhibits IC50 in vitro activities in the assay discussed hereinafter of less than ( less than ) 1.0 xcexcM. This group of compounds is comprised of those compounds of Formula II or a pharmaceutically acceptable salt thereof wherein:
Ar1 is an aryl group that is substituted with a lower hydrocarbyl or halogen (e.g., flourine or chlorine) group;
R1 is hydrido, or lower hydrocarbyl;
R2 is hydrido;
R3 is hydrido or lower hydrocarbyl; and
R4 is aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, or 3-pyridyl lower hydrocarbyl.
A second preferred subclass of compounds within Formula I has structures that correspond to Formula III, or a pharmaceutically acceptable salt thereof wherein: 
R5 is hydrido, C1-C6 hydrocarbyl, or aryl lower hydrocarbyl;
Ar1 is an aryl group that is substituted with a halogen (e.g., chlorine, fluorine or bromine), lower hydrocarbyl, or hydrocarbyloxy group;
R1 is C1-C6 hydrocarbyl; and
R2 is hydrido.
Preferred compounds of Formula III exhibit IC50 in vitro activities in the assay discussed hereinafter and shown in Table I of less than ( less than ) 10 and greater than ( greater than ) 1.0 xcexcM. This group of compounds is comprised of those compounds of Formula III or a pharmaceutically acceptable salt thereof wherein:
Ar1 is an aryl group that is substituted by a lower hydrocarbyl group;
R1 is lower hydrocarbyl;
R2 is hydrido; and
R5 is lower hydrocarbyl or aryl lower hydrocarbyl.
A third subclass of preferred compounds within Formula I have structures represented by Formula IV or a pharmaceutically acceptable salt thereof wherein: 
Ar1 is an aryl group that is substituted by a halogen (e.g., chlorine, fluorine or bromine), lower hydrocarbyl or a hydrocarbyloxy group;
R1 is lower hydrocarbyl; and
R2 is hydrido or lower hydrocarbyl.
Preferred compounds of Formula IV exhibit IC50 in vitro activities in the assay discussed hereinafter and shown in Table I of less than ( less than ) 10 and greater than ( greater than ) 1.0 xcexcM. This group of compounds comprises of those compounds of Formula IV or a pharmaceutically acceptable salt thereof wherein:
Ar1 is an aryl group that is substituted by a lower hydrocarbyl group;
R1 is lower hydrocarbyl; and
R2 is hydrido.
The term xe2x80x9chydridoxe2x80x9d denotes a single hydrogen atom (H). This hydrido radical can be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals can be attached to a carbon atom to form a methylene (xe2x80x94CH2xe2x80x94) radical.
The word xe2x80x9chydrocarbylxe2x80x9d is used herein as a short hand term to include straight and branched chain aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen. Thus, alkyl, alkenyl and alkynyl groups are contemplated, whereas aromatic hydrocarbons such as phenyl and naphthyl groups, which strictly speaking are also hydrocarbyl groups, are referred to herein as aryl groups or radicals, as discussed hereinafter. Where a specific aliphatic hydrocarbyl substituent group is intended, that group is recited; i.e., alkyl, methyl or dodecenyl. Exemplary hydrocarbyl groups contain a chain of 1 to about 12 carbon atoms, and preferably one to about 10 carbon atoms. Most preferred are lower hydrocarbyl radicals that contain one to about six carbon atoms.
Usual chemical suffix nomenclature is followed when using the word xe2x80x9chydrocarbylxe2x80x9d except that the usual practice of removing the terminal xe2x80x9cylxe2x80x9d and adding an appropriate suffix is not always followed because of the possible similarity of a resulting name to one or more substituents. Thus, a hydrocarbyl ether is referred to as a xe2x80x9chydrocarbyloxyxe2x80x9d group rather than a xe2x80x9chydrocarboxyxe2x80x9d group as may possibly be more proper when following the usual rules of chemical nomenclature. On the other hand, a hydrocarbyl group containing a xe2x80x94C(O)xe2x80x94 functionality is referred too as a hydrocarboyl group in as much as there is no ambiguity in using that suffix. As a skilled worker will understand, a substituent that cannot exist such as a C1 alkenyl group is not intended to be encompassed by the word xe2x80x9chydrocarbylxe2x80x9d.
Where used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d, xe2x80x9calkylsulfonylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d and xe2x80x9chydroxyalkylxe2x80x9d, xe2x80x9cthioalkylxe2x80x9d, the term xe2x80x9calkylxe2x80x9d embraces linear or branched saturated radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are radicals having one to about twelve carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.
The term xe2x80x9calkenylxe2x80x9d embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are xe2x80x9clower alkenylxe2x80x9d radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9clower alkenylxe2x80x9d, embrace radicals having xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d orientations, or alternatively, xe2x80x9cExe2x80x9d and xe2x80x9cZxe2x80x9d orientations.
The term xe2x80x9calkynylxe2x80x9d embraces linear or branched radicals having at least one carbon-carbon triple bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are xe2x80x9clower alkynylxe2x80x9d radicals having two to about six carbon atoms. Examples of alkynyl radicals include ethynyl (acetylenyl), propynyl, butynyl and 4-methylbutynyl.
An alkyl group is a particularly preferred hydrocarbyl group. For ease in understanding, alkyl groups are utilized hereinbelow in the explanations of the nomenclature used herein for various substituent groups. It is to be understood, however, that the word xe2x80x9calkylxe2x80x9d is used to stand in for the less familiar word xe2x80x9chydrocarbylxe2x80x9d, which encompasses not only alkyl groups, but also alkenyl and alkynyl groups.
The term xe2x80x9ccycloalkylxe2x80x9d embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are xe2x80x9clower cycloalkylxe2x80x9d radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term xe2x80x9ccycloalkylalkylenexe2x80x9d embraces alkyl radicals substituted with a cycloalkyl radical. More preferred cycloalkylalkylene radicals are xe2x80x9clower cycloalkylalkylenexe2x80x9d, which embrace lower alkyl radicals substituted with a lower cycloalkyl radical as defined above. Examples of such radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
The term xe2x80x9ccycloalkenylxe2x80x9d embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms and one or two double bonds, but not necessarily conjugated (xe2x80x9ccycloalkyldienylxe2x80x9d). More preferred cycloalkenyl radicals are xe2x80x9clower cycloalkenylxe2x80x9d radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
The term xe2x80x9ccycloalkenylalkylenexe2x80x9d embraces alkyl radicals substituted with a cycloalkenyl radical. More preferred cycloalkenylalkylene radicals are xe2x80x9clower cycloalkenylalkylenexe2x80x9d, which embrace lower alkyl radicals substituted with a lower cycloalkenyl radical, as defined above. Examples of such radicals include cyclobutenylmethyl, cyclopentenylmethyl and cyclohexenylmethyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine. The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, can have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms or a combination of different halo radicals. xe2x80x9cLower haloalkylxe2x80x9d embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term xe2x80x9chydroxyalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about twelve carbon atoms, any one of which can be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are xe2x80x9clower hydroxyalkylxe2x80x9d radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkyloxyxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of one to about twelve carbon atoms. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
The term xe2x80x9calkoxyalkylxe2x80x9d embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical to form, for example, monoalkoxyalkyl and dialkoxyalkyl radicals. The xe2x80x9calkoxyxe2x80x9d radicals can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d radicals.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings can be attached together in a pendent manner or can be fused. More preferred aryl are 6-12 membered aryl radicals. Examples of such radicals include phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Phenyl radicals are preferred aryl radicals.
Aryl moieties can also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.
The term xe2x80x9cheterocyclylxe2x80x9d embraces saturated, partially unsaturated and aromatically-unsaturated heteroatom-containing ring-shaped radicals, which can also be called xe2x80x9cheterocyclylxe2x80x9d, xe2x80x9cheterocycloalkenylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d respectively, where the heteroatoms are nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicals can include a tetravalent nitrogen, such as in tetrazolium and pyridinium radicals.
The term xe2x80x9cheteroarylxe2x80x9d embraces aromatically-unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 5- to 10-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), and the like; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl), and the like; an unsaturated 5- or 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl or furyl; unsaturated 5- or 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl) and the like; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, and 1,2,5-thiadiazolyl) and the like; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl or benzothiadiazolyl) and the like.
The term xe2x80x9cheteroarylxe2x80x9d also embraces radicals where heterocyclyl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
A heterocyclyl group can have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino. The term xe2x80x9cheterocyclylalkylenexe2x80x9d embraces heterocyclyl-substituted alkyl radicals. More preferred heterocyclylalkylene radicals are xe2x80x9clower heterocyclylalkylenexe2x80x9d radicals having one to six carbon atoms and a heterocyclyl radical.
The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to about twelve carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are xe2x80x9clower alkylthioxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.
The term xe2x80x9calkylthioalkylenexe2x80x9d embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about twelve carbon atoms. More preferred alkylthioalkylene radicals are xe2x80x9clower alkylthioalkylenexe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkylene radicals include methylthiomethyl.
The term xe2x80x9calkylsulfinylxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to about twelve carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 radical. More preferred alkylsulfinyl radicals are xe2x80x9clower alkylsulfinylxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.
The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms such as xe2x80x9calkylsulfonylxe2x80x9d, or xe2x80x9chalosulfonylxe2x80x9d denotes a divalent radical, xe2x80x94SO2xe2x80x94. xe2x80x9cAlkylsulfonylxe2x80x9d embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are xe2x80x9clower alkylsulfonylxe2x80x9d radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The xe2x80x9calkylsulfonylxe2x80x9d radicals can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals. The term xe2x80x9chalosulfonylxe2x80x9d embraces halo radicals attached to a sulfonyl radical. Examples of such halosulfonyl radicals include chlorosulfonyl and bromosulfonyl.
The terms xe2x80x9csulfamylxe2x80x9d, xe2x80x9caminosulfonylxe2x80x9d and xe2x80x9csulfonamidylxe2x80x9d denote NH2O2Sxe2x80x94. The term xe2x80x9ccarbonylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9calkoxycarbonylxe2x80x9d, denotes xe2x80x94(Cxe2x95x90O)xe2x80x94. The terms xe2x80x9ccarboxyxe2x80x9d or xe2x80x9ccarboxylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9ccarboxyalkylxe2x80x9d, denotes xe2x80x94CO2xe2x80x94. The term xe2x80x9ccarboxyalkylxe2x80x9d, embraces alkyl radicals substituted with a carboxy radical. More preferred are xe2x80x9clower carboxyalkylxe2x80x9d, radicals that embrace carboxy-substituted lower alkyl radicals, as defined above. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl.
The term xe2x80x9calkoxycarbonylxe2x80x9d means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are xe2x80x9clower alkoxycarbonylxe2x80x9d radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl (ester) radicals include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
The term xe2x80x9calkoxycarbonylalkylenexe2x80x9d embraces alkyl radicals substituted with an alkoxycarbonyl radical as defined above. More preferred are xe2x80x9clower alkoxycarbonylalkylenexe2x80x9d radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonylalkylene radicals include methoxycarbonylmethylene, ethoxycarbonylmethylene, methoxycarbonylethylene and ethoxycarbonylethylene.
The term xe2x80x9calkylcarbonylxe2x80x9d, includes radicals having alkyl radicals attached to a carbonyl radical. Examples of such radicals include methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, and pentylcarbonyl.
The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferred aralkyl radicals are xe2x80x9clower aralkylxe2x80x9d, having lower alkyl groups substituted with one or more aryl groups. Examples of such groups include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in such an aralkyl group can be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy moieties. The terms benzyl and phenylmethyl are interchangeable.
The term xe2x80x9cheterocyclylalkylenexe2x80x9d embraces saturated, partially unsaturated and unsaturated heterocyclyl-substituted alkyl radicals such as pyrrolidinylmethyl, pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in heteroaralkyl (unsaturated heterocyclyl-substituted alkyl radicals) can be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy groups.
The term xe2x80x9caryloxyxe2x80x9d embraces aryl radicals attached through an oxygen atom to other radicals. The term xe2x80x9caralkoxyxe2x80x9d embraces aralkyl radicals attached through an oxygen atom to other radicals.
The term xe2x80x9caminoalkylxe2x80x9d embraces alkyl radicals substituted with amino radicals. More preferred are xe2x80x9clower aminoalkylxe2x80x9d radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term xe2x80x9calkylaminoxe2x80x9d denotes amino groups that are substituted with one or two alkyl radicals. Preferred are xe2x80x9clower alkylaminoxe2x80x9d radicals having alkyl portions having one to six carbon atoms. Suitable lower alkylamino radicals can be monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
The term xe2x80x9carylaminoxe2x80x9d denotes amino groups that are substituted with one or two aryl radicals, such as N-phenylamino. The xe2x80x9carylaminoxe2x80x9d radicals can be further substituted on the aryl ring portion of the radical as discussed previously for other aryl-containing radicals.
The term xe2x80x9caminocarbonylxe2x80x9d denotes an amide group of the formula xe2x80x94C(xe2x95x90O)NH2. The term xe2x80x9calkylaminocarbonylxe2x80x9d denotes an aminocarbonyl group that has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are xe2x80x9cN-alkylaminocarbonylxe2x80x9d and xe2x80x9cN,N-dialkylaminocarbonylxe2x80x9d, radicals. More preferred are xe2x80x9clower N-alkylaminocarbonylxe2x80x9d and xe2x80x9clower N,N-dialkylaminocarbonylxe2x80x9d radicals with lower alkyl portions as defined above.
The term xe2x80x9calkylcarbonylaminoxe2x80x9d embraces amino groups that are substituted with one or more alkylcarbonyl radicals. More preferred alkylcarbonylamino radicals are xe2x80x9clower alkylcarbonylaminoxe2x80x9d having lower alkylcarbonyl radicals as defined above attached to amino radicals. The term xe2x80x9calkylaminoalkylenexe2x80x9d embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
Tables 1 through 14 hereinafter illustrate compounds of Formulas II, III and IV that illustrate preferred substituent groups other than hydrido for one of substituents Ar1, R1, R2, R3, R4, and R5. The remaining groups Ar1, R1, R2, R3, R4, and R5 illustrated for each structure shown in a compound table are as discussed elsewhere herein.
Treatment Process
The present invention also contemplates a process for the treatment of a TNF-mediated disorder or a p38 kinase-mediated disorder, such as arthritis. That process comprises administering a therapeutically-effective amount (a p38 MAP kinase enzyme-inhibiting effective amount) of a compound of Formula I, or a pharmaceutically-acceptable salt thereof, to a mammalian host having such a condition. A mixture of such compounds can also be used. The use of administration repeated a plurality of times is particularly contemplated.
Also included in the family of compounds of Formula I (and also Formulas II, III and IV) are the pharmaceutically-acceptable salts of those compounds, as noted previously. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I can be prepared from an inorganic acid or from an organic acid.
Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes of organic acids. Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, hydroxybutyric, galactaric and galacturonic acids.
Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic ion salts and organic ion salts. More preferred metallic ion salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metal ions. Such salts can be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by conventional means from the corresponding compound of Formula I by reacting for example, the appropriate acid or base with the compound of Formula I.
A compound of Formula I is preferably administered in a pharmaceutical composition. Such a composition contains a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
Thus, also embraced within this invention is a class of pharmaceutical compositions comprising a compound of Formula I as active ingredient (agent or compound) in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) and, if desired, other active ingredients.
The active compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition can, for example, be administered orally, intravascularly (IV), intraperitoneally, subcutaneously, intramuscularly (IM) or topically.
For oral administration, the pharmaceutical composition can be in the form of, for example, a tablet, hard or soft capsule, lozenges, dispensable powders, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.
The active ingredient can also be administered by injection (IV, IM, subcutaneous or jet) as a composition wherein, for example, saline, dextrose, or water can be used as a suitable carrier. The pH value of the composition can be adjusted, if necessary, with suitable acid, base, or buffer. Suitable bulking, dispersing, wetting or suspending agents, including mannitol and PEG 400, can also be included in the composition. A suitable parenteral composition can also include a compound formulated as a sterile solid substance, including lyophilized powder, in injection vials. Aqueous solution can be added to dissolve the compound prior to injection.
The amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus can vary widely.
A pharmaceutical composition can contain an active compound at about 0.1 to 1000 mg, preferably at about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight, and most preferably between about 0.5 to 30 mg/kg body weight, can be appropriate. The daily dose can be administered in one to four doses per day.
In the case of skin conditions, it can be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. For disorders of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
When formulated in an ointment, the active ingredients can be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
The topical formulation can desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
The compounds of this invention can also be administered by a transdermal device. Preferably, topical administration is accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent can also function as the membrane. The transdermal patch can include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch.
The oily phase of the emulsions of this invention can be constituted from known ingredients in a known manner. Although the phase can comprise merely an emulsifier, it can comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween(trademark) 60, Span(trademark) 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters can be used. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.
For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds can be admixed with lactose, sucrose, starch-powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Preparation of Useful Compounds
Schemes I through IX hereinbelow illustrate chemical processes and transformations that can be useful for the preparation of compounds useful in this invention; i.e., compounds of Formulas I, wherein R1, and R2, substituent and Ar1, are as defined for Formula I, except where noted. 
Scheme I shows the synthesis of a 1,5-diaryl pyrazole (5) wherein a pyridine ring is attached to position 5 of the pyrazole ring, R1 is lower alkyl and R2 is hydrido or lower alkyl. The synthesis is carried out by condensing an appropriate ketone (2) with methyl isonicotinate (1) in the presence of a suitable base to provide the diketone 3. Examples of appropriate ketones include acetone, methyl ethyl ketone, diethyl ketone and the like. Examples of suitable bases include sodium methoxide, and sodium ethoxide and the like. Suitable solvents for this reaction include tetrahydrofuran (THF) or methanol (MeOH) at temperatures ranging from room temperature to reflux. Treatment of diketone 3 with an aryl hydrazine derivative 4, in a suitable solvent at temperatures ranging up to reflux provides a 1,5-diaryl pyrazole, compound 5. Examples of suitable solvents for this reaction include ethanol, acetic acid, ethanol-acetic acid mixtures and the like. Substitution on Ar1 in 5 is controlled by proper selection of the starting hydrazine 4. When R2 of ketone 2 is hydrido, then R2 of pyrazole 5 is hydrido. 
Scheme II illustrates the synthesis of a pyrazole, compound 8 wherein R2 is a lower alkyl group and R1 is hydrido or lower alkyl. Compounds wherein R1 is hydrido and R2 is a lower alkyl group can be synthesized by treatment of pyridyl ketone 6 with dimethylformamide dimethyl acetal (DMF acetal). Examples of suitable pyridyl ketones 6 include propionyl pyridine and butanoyl pyridine. This reaction can be carried out in the DMF acetal itself or in a suitable solvent such as dimethylformamide. This provides enamine 7 which is convertible to pyridyl pyrazole 8 by reaction with a suitably substituted phenylhydrazine. This step can be carried out as described for Scheme I and substitution on Ar1 of pyrazole 8 is controlled by selection of a properly substituted hydrazine. Scheme II also describes the synthesis of pyrazoles wherein both R1 and R2 are lower alkyl groups. This is achieved by reacting ketone 6 with a carboxylic acid ester, such as methyl acetate or methyl propionate or the like, in the presence of a base, such as sodium methoxide, in a suitable solvent, such as methanol or tetrahydrofuran. The resulting diketone 7a is converted to pyrazole 8 (R1 and R2 are lower alkyl) using the procedure described above. 
Scheme III shows the synthesis of a pyrazole, compound 13, analogs of compound 5 in which the pyridine 10 ring bears a chlorine atom at position 2. 2-Chloropyridine-4-carboxylic acid, compound 9, is treated with thionyl chloride in a solvent such as toluene, and heated to reflux to give 2-chloropyridine-4-carboxylic acid chloride, compound 10, which is then converted to methyl 2-chloroisonicotinate, compound 11. Compound 11 is treated with a ketone 2 in the presence of a base such as sodium methoxide in a solvent such as tetrahydrofuran, at temperatures ranging from 25xc2x0 C. up to reflux to provide a diketone, compound 12. Treatment of the diketone, compound 12, with an arylhydrazine derivative 4 in ethanol or other suitable solvent at a temperature ranging up to reflux, provides pyrazole compound 13. When R2 of ketone 2 is hydrido, then R2 of 13 is hydrido. 
Scheme IV shows the syntheses of various pyrazole derivatives from compound 13 by manipulations on its 2-chloropyridine ring. The chlorine atom is a labile group and can be displaced with various nucleophiles to provide 2-substituted pyridine derivatives. When compound 13 is treated with an amine 14 at a temperature of usually about 100 to about 200xc2x0 C. and at a pressure of about 70 to about 200 (or higher) psi in xylene, pyrazole 15 is formed. Examplary substituents for R3 of amine 14 are hydrogen, lower alkyl, hydroxyalkyl, or aralkyl.
When R3 is benzyl, hydrogenation of the compound removes the benzyl group and forms the amino compound 16. When the benzyl group bears a para methoxy substituent, an alternative method of removal of the benzyl group is treatment with refluxing trifluoroacetic acid.
Treatment of compound 13 with an alcohol 17 in the presence of a base in a suitable solvent provides pyrazole compound 18. Examples of suitable alcohols are benzyl alcohol and methanol. Suitable bases include triethylamine and pyridine.
Compound 13 can also be treated with a sulfinic acid sodium salt derivative, compound 19, in a suitable solvent such as dimethylformamide (DMF) at an elevated temperature to provide pyrazole compound 20. An example of a sulfinic acid sodium salt is sodium methane sulfinate and its reaction leads to methyl sulfone.
Finally, treatment of compound 13 with sodium azide in a suitable solvent such as DMF, provides azido pyridine 21. 
Scheme V shows the preparation of pyrazole compounds 31 and 32 bearing hydroxy and methoxy substituents at position 2 of the pyridine ring. Treatment of methyl 2-methoxyisonicotinate compound 29, which is derived from methyl 2-chloroisonicotinate, compound 28, with a ketone, compound 2, provides compound 30, a diketone. Compound 30 is treated with an arylhydrazine derivative, compound 4, under the standard condition as described in the previous synthetic schemes, to yield pyrazole 31. Treatment of compound 31 with an acid such as hydrochloric acid provides pyrazole 32 which bears a hydroxyl at position 2 of the pyridine ring. When R2 of ketone 2 is hydrogen (hydrido), then R2 of pyrazoles 31 and 32 is hydrogen (hydrido). 
Scheme VI demonstrates the syntheses of the pyrazole compounds 37 and 38 that bear cyano and carboxamido substituents, respectively, at position 2 of the pyridine ring. Methyl 2-cyanoisonicotinate 35 is synthesized from methyl isonicotinate 33 in two steps by oxidation with hydrogen peroxide in an acid solvent, such as acetic acid. The resulting pyridine N-oxide 34 is treated with dimethylcarbamoyl chloride in the presence of trimethylsilylcyanide to provide ester 35. Treatment of ester 35 with ketone 2 according to general conditions described for similar reactions in the preceding schemes gives diketone 36. Treatment of 36 with a substituted arylhydrazine produces pyrazole 37. Desired substitution on Ar1 is achieved by selection of the properly substituted arylhydrazine.
Cyano pyrazole 37 is converted to the carboxamido compound 38 by oxidation with hydrogen peroxide in the presence of a base. Suitable bases include sodium carbonate, potassium carbonate and sodium hydroxide. Manipulation of substituent R2 is effected by selection of the proper ketone 2. When R2 of compound 2 is hydrogen, R2 in pyrazoles 37 and 38 is hydrogen (hydrido). 
Scheme VII illustrates a two-step synthesis of 3-amino-1,5-diarylpyrazoles 40. In the first step, 4-acetylpyridine (A, R2=H) is treated with a suitable base to generate an enolate anion. Examples of suitable bases include lithium hexamethyl disilazide, sodium hexamethyldisilazide and lithium diisopropylamide. Suitable solvents for this reaction include tetrahydrofuran and diethyl ether. The resulting intermediate enolate anion is treated with a suitable isothiocyanate to give beta keto thioamide 39. Examples of suitable isothiocyanates include ethyl isothiocyanate and trimethylsilylisothicyanate. The reaction of thioamide 39 with an arylhydrazine 4 leads to the formation of pyrazole 40. This reaction is carried out using conditions discussed in preceding examples. Control of substitution on Ar1 is effected by proper selection of the substituted phenylhydrazine.
When an alkyl isothiocyanate is employed in this sequence, R of compound 40 is an alkyl group. When trimethylsilyl isothiocyanate is employed, R of 40 is a trimethylsilyl group, which is easily removed to produce the primary amino compound where R of compound 40 is hydrogen. Examples of reaction conditions used to remove the silyl group are acetic acid in water and tetrahydrofuran or aqueous sodium bisulfate. When R2 of the starting pyridyl ketone is a substituent other than H, that substituent becomes the substituent R2 at the 4 position of the pyrazole 40. 
Scheme VIII illustrates the synthesis of a 1,5-diaryl pyrazole wherein R2 is a derivatized carboxyl group or an amino group. An ester of isonicotinic acid is treated with a carboxylic acid ester in the presence of a base to produce beta keto ester 41. Suitable esters of isonicotinic acid include the methyl and ethyl esters and the like. Suitable esters of the carboxylic acid also include the methyl and ethyl esters. Bases such as sodium methoxide and sodium ethoxide are suitable for this reaction. The reaction can be carried out in an alcoholic solvent such as methanol or ethanol. Ketoester 41 is converted to the enamine intermediate 42 by reaction with dimethylformamide dimethylacetal either neat or in a solvent such as dimethyl formamide. Reaction with a properly substituted arylhydrazine 4 produces the carboxylic acid ester 43. Reaction of this ester with various amines, such as piperazine produces amides 44 (R=substituted amine).
Similarly, saponification of 43 produces acid B. Saponification can be carried out using a base such as sodium hydroxide in an aqueous solvent such as aqueous methanol or ethanol or the like. Acid B is converted to amine C by reaction with diphenylphosporyl azide (DPPA) in the presence of a base such as triethylamine in a solvent such as tetrahydrofuran or dioxane. 
Scheme IX illustrates the synthesis of a 4-amino-1,5-diarylpyraozle, compound 48. In step 1, 4-acetylpyridine is brominated with bromine in the presence of a solvent such as 48 percent hydrobromic acid to provide the bromoketone, compound 45. In step 2, the reaction of compound 45 with an amine, such N-tert-butoxycarbonylpiperazine, in the presence of a base such as triethylamine, and in the presence of a solvent such as DMF, provides intermediate compound 46. Other suitable amines include piperidine and dimethylamine. In step 3, the reaction of intermediate compound 46 with dimethylformamide dimethylacetal (DMF-DMA) in a solvent such as tetrahydrofuran or dimethyformamide provides intermediate enamine 47. In step 4, the condensation of intermediate compound 47 with a substituted arylhydrazine such as 4-fluorophenylhydrazine, in a solvent such as ethanol provides desired pyrazole, compound 48.
It should be recognized that in the above Schemes, the pyridine ring can be replaced by a pyrimidine ring when suitably substituted pyrimidine starting materials are employed. Suitable starting materials are recognizable by one skilled in the art and their syntheses are readily accessible in the scientific literature. For example, the ethyl ester of pyrimidine-4-carboxylic acid can be synthesized according to procedures described by Wong et al, J. Org. Chem., vol. 30, p. 2398 (1965). The methyl ester of 2-methoxypyrimidine-4-carboxylic acid is described by Warczykowski and Wojciechowski, Pol. J. Chem., vol. 54, pp. 335-340 (1980). The synthesis of 2-diethylaminopyrimidine-4-carboxylic acid from 2-chloropyrimidine-4-carbonitrile is also described in that paper. The synthesis of 2-aminopyrimidine-4-carboxylic acid from 2-chloropyrimidine-4-carbonitrile is described by Daves et al., in J. Het. Chem., vol. 1, p. 130 (1964). The synthesis of 2-chloropyrimidine-4-carbonitrile is described by D. J. Brown et al, Aust. J. Chem., vol. 37, pp. 155-163 (1984) and by A. E. Friesen et al., Tetrahedron, vol. 45, pp. 5151-5162 (1989). The conversion of 2-methylpyrimidine-4-carboxylic acid methyl ester to a 1,3-diketone by reaction with the enolate anion of acetophenone is described by T. Sakamoto, Chem. Pharm. Bull., vol. 30, pp. 1033-1035 (1982).